The goal of this proposal is to investigate the mechanism of action of a natural product derived from citrus pectin in overcoming galectin-3 mediated resistance to apoptosis in lymphoma, and to understand the interaction of this natural product with conventional cancer agents. Galectin-3, a member of the galectin family of mammalian lectins, promotes cell survival, so that galectin-3 overexpression promotes tumor cell resistance to apoptosis and thus resistance to many conventional chemotherapeutic agents. Galectin-3 is highly overexpressed in a specific type of lymphoma, termed diffuse large B cell lymphoma (DLBCL) and promotes apoptosis resistance in DLBCL cells. However, the mechanism by which galectin-3 expression promotes apoptosis resistance is unknown. A modified citrus pectin that selectively inhibits galectin-3 mediated cell-cell interactions in various animal models of metastatic cancer has been developed as a novel therapeutic compound, termed GCS-100, that is currently in clinical trials for hematologic malignancies. However, there is little information on the mechanism by which this pectin-derived polysaccharide inhibits galectin-3, or the interaction of this natural product with conventional cancer therapies. The goal of this R21 application is to perform preclinical studies to advance our knowledge of the mechanism of action of GCS-100 on lymphoma cells, using both human lymphoma cell lines and primary patient samples. Specifically, we will 1) Identify the subcellular localization of galectin-3 in B lymphoma cells, and determine the effect of GCS-100 on the amount and distribution of galectin-3 in these cells;2) Characterize the mechanism of galectin-3 mediated apoptosis resistance in B lymphoma cells and determine how GCS-100 antagonizes the anti-apoptotic action of galectin-3;3) Investigate the role of galectin-3 in cell survival and disease progression in primary DLBCL patient samples, to characterize patient populations that could benefit from GCS-100. Understanding how GCS-100 antagonizes pro-survival functions of galectin-3 will also help to elucidate how galectin-3 expression makes tumor cells resistant to apoptosis. This R21 application is thus highly responsive to PA-06-400, "Developmental Projects in Complementary Approaches to Cancer Care". PUBLIC HEALTH RELEVANCE: Novel therapies are needed for a group of cancers termed lymphomas, as many patients with this disease fail to respond to conventional cancer therapies. We will investigate a natural product therapeutic, derived from citrus pectin, for the ability to sensitize lymphoma cells to the effects of conventional cancer therapies and thus potentially enhance the response to treatment and survival of lymphoma patients.